Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, 160 East 34th Street, New York, NY, 10016, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Breast Cancer Res Treat. 2018 Feb;168(1):57-67. doi: 10.1007/s10549-017-4570-4. Epub 2017 Nov 9.
Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant challenge. Prior studies have shown that low-dose oral cyclophosphamide can transiently deplete regulatory T cells (Tregs) and improve anti-tumor immunity. We investigated the combination of exemestane with cyclophosphamide in patients with advanced HR-positive breast cancer and assessed changes in circulating immune cell subsets.
This was a single-arm phase II trial of exemestane with cyclophosphamide in patients with metastatic HR-positive/HER2-negative breast cancer who had progressed on prior endocrine therapy (ClinicalTrials.gov: NCT01963481). Primary endpoint was progression-free survival (PFS) at 3 months (RECIST 1.1). Secondary objectives included median PFS, objective response rate, duration of response, and safety. Circulating Tregs (FOXP3Helios) and other immune cell subsets were monitored during treatment and compared with healthy controls.
Twenty-three patients were enrolled. Treatment was well tolerated, without grade 4/5 toxicities. Objective responses were seen in 6/23 patients (26.1%; 95% CI 10.2-48.4%) and were durable (median 11.6 months). Three-month PFS rate was 50.1% (95% CI 33.0-76.0%); median PFS was 4.23 months (95% CI 2.8-11.7). No treatment-related decrease in Tregs was observed. However, elevated baseline levels of Naïve Tregs [greater than 2.5 (the median of the naïve Tregs)] were associated with relative risk of disease progression or death [hazard ratio 11.46 (95% CI 2.32-56.5)]. In addition, the baseline levels of Naïve Tregs (adj-p = 0.04), Memory Tregs (adj-p = 0.003), CD4 + Central Memory T cells (adj-p = 0.0004), PD-1 + CD4 + Central Memory T cells (adj-p = 0.008), and PD-1 + CD4 + Effector Memory T cells (adj-p = 0.009) were significantly greater in the patients than in the healthy controls; the baseline levels of %CD4 + Naïve T cells (adj-p = 0.0004) were significantly lower in patients compared with healthy controls (n = 40).
Treg depletion was not observed with low-dose cyclophosphamide when assessed by the specific marker FOXP3 + Helios +; however, baseline naïve Tregs were associated with 3-month PFS. Exemestane/cyclophosphamide combination had favorable safety profile with evidence of clinical activity in heavily pretreated patients.
激素受体（HR）阳性乳腺癌对内分泌治疗的耐药性是一个重大挑战。先前的研究表明，低剂量口服环磷酰胺可以短暂耗尽调节性 T 细胞（Tregs）并改善抗肿瘤免疫。我们研究了在晚期 HR 阳性乳腺癌患者中联合使用依西美坦和环磷酰胺，并评估了循环免疫细胞亚群的变化。
这是一项单臂、II 期试验，在先前内分泌治疗进展的转移性 HR 阳性/HER2 阴性乳腺癌患者中使用依西美坦联合环磷酰胺（ClinicalTrials.gov：NCT01963481）。主要终点是 3 个月时的无进展生存期（PFS）（RECIST 1.1）。次要目标包括中位 PFS、客观缓解率、缓解持续时间和安全性。在治疗期间监测循环 Tregs（FOXP3Helios）和其他免疫细胞亚群，并与健康对照进行比较。
共纳入 23 例患者。治疗耐受性良好，无 4/5 级毒性。23 例患者中有 6 例（26.1%；95%CI 10.2-48.4%）观察到客观缓解，缓解持久（中位 11.6 个月）。3 个月时 PFS 率为 50.1%（95%CI 33.0-76.0%）；中位 PFS 为 4.23 个月（95%CI 2.8-11.7）。未观察到与治疗相关的 Tregs 减少。然而，基线时升高的幼稚 Tregs [大于 2.5（幼稚 Tregs 的中位数）]与疾病进展或死亡的相对风险相关[风险比 11.46（95%CI 2.32-56.5）]。此外，基线时幼稚 Tregs（调整后 p=0.04）、记忆 Tregs（调整后 p=0.003）、CD4+中央记忆 T 细胞（调整后 p=0.0004）、PD-1+CD4+中央记忆 T 细胞（调整后 p=0.008）和 PD-1+CD4+效应记忆 T 细胞（调整后 p=0.009）的水平在患者中显著高于健康对照组；与健康对照组相比，患者的%CD4+幼稚 T 细胞（调整后 p=0.0004）水平显著降低（n=40）。
当使用特定标志物 FOXP3+Helios+评估时，低剂量环磷酰胺未观察到 Treg 耗竭；然而，基线时幼稚 Tregs 与 3 个月时的 PFS 相关。依西美坦/环磷酰胺联合治疗具有良好的安全性，在接受过多线治疗的患者中显示出临床活性。
